Neuronal dendrites and synapses are structurally distorted in individuals with mental retardation and other neurological disorders. Dendrites and synapses also differ greatly in their appearance in normal brains. Hence, variability in structure-function relationships must be understood in the normal brain to be able to draw conclusions about the distortions. A rigorous plan is proposed to identify structure- function relationships along dendrites in the mature hippocampus, a brain region long known to be involved in learning and memory. Six core subcellular structures will be investigated along dendrites and into dendritic spines that host excitory synapses, including microtubules for transport, polyribosomes for protein synthesis, Golgi apparatus for posttranslational modifications, endosomes for membrane recycling, and smooth endoplasmic reticulum (SER) and mitochondria for calcium regulation. Connectivity relationships among dendrites, axons and perisynaptic astroglia will also be discerned. Several recent findings from this laboratory reveal the power of serial section transmission electron microscopy (ssTEM) to investigate these relationships. Dendrites containing more microtubules had more synapses. Dendritic spines with polyribosomes or perisynaptic astroglia had larger synapses. Different spines contained endosomes from those containing SER. Only large, mature spines contained a spine apparatus, which is similar to the Golgi apparatus. A cellular memory mechanism, known as long-term potentiation (LTP), enhanced several of these relationships in both mature and immature hippocampus. New dendritic spines formed and existing spine synapses enlarged by 5-30 minutes after the induction of LTP. Spine membrane was supplied from local recycling endosomes. Only spines that acquired polyribosomes had enlarged synapses two hours later. Here it is proposed to determine whether this structural plasticity relates to recognized distance- dependent changes in dendritic function and caliber among dendrites in the mature hippocampal area CA1. We will assess whether or not dendrites of varying caliber have different levels of structural plasticity after the induction of LTP. We will ascertain whether dendrites with more or larger synapses connect with more of the axons surrounding them after the induction of LTP. We will determine distance-dependent differences in dendrite structure, composition, and connectivity throughout the CA1 apical and basilar dendritic arbors. We will enhance and develop new Neuroinformatics tools to collect and share these content-rich data. We predict greater understanding will emerge about distance dependent dendritic and synaptic structure and function. PUBLIC HEALTH RELEVANCE Neuronal dendrites and synapses appear structurally distorted in individuals with mental retardation and other neurological disorders. Dendrites and synapses are also structurally diverse in normal brains;hence the variability in structure-function relationships must be understood to draw meaningful conclusions about these distortions. A rigorous plan is proposed to use neuroinformatics tools and three-dimensional reconstruction to identify important structure-function relationships along the length of dendrites, at their synapses, and with their neighboring axons and astroglia during long-term potentiation, a well-studied cellular mechanism of learning and memory.